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1.
Invest Ophthalmol Vis Sci. 2018 Jun 1;59(7):2999-3010. doi: 10.1167/iovs.18-23829.

D-cis-Diltiazem Can Produce Oxidative Stress in Healthy Depolarized Rods In Vivo.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
3
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, United States.
4
Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.

Abstract

Purpose:

New perspectives are needed to understand decades of contradictory reports on the neuroprotective effects of the Cav1.2 L-type calcium channel blocker d-cis-diltiazem in retinitis pigmentosa (RP) models. Here, we address, in vivo, the following two knowledge gaps regarding d-cis-diltiazem's actions in the murine outer retina: (1) do normal mouse rods contain d-cis-diltiazem-insensitive Cav1.2 L-type calcium channels? (2) Can d-cis-diltiazem modify the normal rod redox environment?

Methods:

First, transretinal Cav1.2 L-type calcium channels were noninvasively mapped with manganese-enhanced magnetic resonance imaging (MRI) following agonist Bay K 8644 in C57BL/6 (B6) and in Cav1.2 L-type calcium channel BAY K 8644-insensitive mutant B6 mice. Second, d-cis-diltiazem-treated oxidative stress-vulnerable (B6) or -resistant [129S6 (S6)] mice were examined in vivo (QUEnch-assiSTed [QUEST] MRI) and in whole retina ex vivo (lucigenin). Retinal thickness was measured using MRI.

Results:

The following results were observed: (1) manganese uptake patterns in BAY K 8644-treated controls and mutant mice identified in vivo Cav1.2 L-type calcium channels in inner and outer retina; and (2) d-cis-diltiazem induced rod oxidative stress in dark-adapted B6 mice but not in light-adapted B6 mice or dark-adapted S6 mice (QUEST MRI). Oxidative stress in vivo was limited to inferior outer retina in dark-adapted B6 mice approximately 1-hour post d-cis-diltiazem. By approximately 4 hours post, only superior outer retina oxidative stress was observed and whole retinal superoxide production was supernormal. All groups had unremarkable retinal thicknesses.

Conclusions:

D-cis-diltiazem's unexpectedly complex spatiotemporal outer retinal oxidative stress pattern in vivo was dependent on genetic background and rod membrane depolarization, but not apparently dependent on Cav1.2 L-type calcium channels, providing a potential rationale for contradictory results in different RP models.

2.
J Magn Reson. 2018 Jun;291:94-100. doi: 10.1016/j.jmr.2018.01.013. Epub 2018 Apr 26.

Oxidative stress measured in vivo without an exogenous contrast agent using QUEST MRI.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI 48201, United States; Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI 48201, United States. Electronic address: baberko@med.wayne.edu.

Abstract

Decades of experimental studies have implicated excessive generation of reactive oxygen species (ROS) in the decline of tissue function during normal aging, and as a pathogenic factor in a vast array of fatal or debilitating morbidities. This massive body of work has important clinical implications since many antioxidants are FDA approved, readily cross blood-tissue barriers, and are effective at improving disease outcomes. Yet, the potential benefits of antioxidants have remained largely unrealized in patients because conventional methods cannot determine the dose, timing, and drug combinations to be used in clinical trials to localize and decrease oxidative stress. To address this major problem and improve translational success, new methods are urgently needed that non-invasively measure the same ROS biomarker both in animal models and patients with high spatial resolution. Here, we summarize a transformative solution based on a novel method: QUEnch-assiSTed MRI (QUEST MRI). The QUEST MRI index is a significant antioxidant-induced improvement in pathophysiology, or a reduction in 1/T1 (i.e., R1). The latter form of QUEST MRI provides a unique measure of uncontrolled production of endogenous, paramagnetic reactive oxygen species (ROS). QUEST MRI results to-date have been validated by gold standard oxidative stress assays. QUEST MRI has high translational potential because it does not use an exogenous contrast agent and requires only standard MRI equipment. Summarizing, QUEST MRI is a powerful non-invasive approach with unprecedented potential for (i) bridging antioxidant treatment in animal models and patients, (ii) identifying tissue subregions exhibiting oxidative stress, and (iii) coupling oxidative stress localization with behavioral dysfunction, disease pathology, and genetic vulnerabilities to serve as a marker of susceptibility.

KEYWORDS:

Brain; Free radicals; Oxidative stress; Reactive oxygen species; Retina

3.
Invest Ophthalmol Vis Sci. 2018 Mar 1;59(3):1659-1665. doi: 10.1167/iovs.17-22734.

Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6brd10 Mice.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
3
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, United States.

Abstract

Purpose:

In cyclic light-reared Pde6brd10 mice, rod cell oxidative stress contributes to the degenerative phenotype. Dark rearing Pde6brd10 mice slows but does not prevent atrophy. This suggests that outer retinal oxidative stress occurs in Pde6brd10 mice independent of light exposure, a hypothesis tested in this study.

Methods:

Mouse strains Pde6brd10 and C57Bl/6 (wild type) were dark reared until postnatal day (P) 23 (P23) or P30. In subgroups of dark-reared mice, (1) layer-specific excessive free radical production (i.e., an oxidative stress biomarker) in vivo via QUEnch-assiSTed magnetic resonance imaging (QUEST MRI) was indicated by a significant reduction in the greater-than-normal spin-lattice relaxation rate R1 (1/T1) with methylene blue, (2) superoxide production was measured ex vivo in whole retina (lucigenin), and (3) retinal layer spacing and thickness were assessed in vivo (optical coherence tomography, MRI).

Results:

In P23 male Pde6brd10 mice, only the outer superior retina showed oxidative stress in vivo, as measured by QUEST MRI; a lucigenin assay confirmed supernormal superoxide production. In contrast, at P30, no evidence for retinal oxidative stress was observed. In P23 female Pde6brd10 mice, no retinal oxidative stress was apparent; however, at P30, oxidative stress was observed in superior inner and outer nuclear layers. Male and female Pde6brd10 mice at P23 had normal retinal thicknesses, whereas at P30, modest thinning was noted in inferior and superior retina.

Conclusions:

We confirmed that outer retinal oxidative stress occurs in male and female dark-reared Pde6brd10 mice. Male and female Pde6brd10 mice demonstrated similar degrees of retinal thinning, but with unexpectedly distinct spatial and temporal retinal oxidative stress patterns.

4.
Brain Imaging Behav. 2018 Mar 28. doi: 10.1007/s11682-018-9856-6. [Epub ahead of print]

Calcium/calmodulin-stimulated adenylyl cyclases 1 and 8 regulate reward-related brain activity and ethanol consumption.

Author information

1
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA.
2
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
4
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
5
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
6
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
7
Research & Development Service, John D. Dingell VA Medical Center, Detroit, MI, USA. alana.conti@wayne.edu.
8
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA. alana.conti@wayne.edu.
9
Department of Neurosurgery, Wayne State University, 4646 John R St., Detroit, MI, 48201, USA. alana.conti@wayne.edu.

Abstract

Evidence suggests a predictive link between elevated basal activity within reward-related networks (e.g., cortico-basal ganglia-thalamic networks) and vulnerability for alcoholism. Both calcium channel function and cyclic adenosine monophosphate (cAMP)/protein kinase A-mediated signaling are critical modulators of reward neurocircuitry and reward-related behaviors. Calcium/calmodulin-stimulated adenylyl cyclases (AC) 1 and 8 are sensitive to activity-dependent increases in intracellular calcium and catalyze cAMP production. Therefore, we hypothesized AC1 and 8 regulate brain activity in reward regions of the cortico-basal ganglia-thalamic circuit and that this regulatory influence predicts voluntary ethanol drinking responses. This hypothesis was evaluated by manganese-enhanced magnetic resonance imaging and chronic, intermittent ethanol access procedures. Ethanol-naïve mice with genetic deletion of both AC1 and 8 (DKO mice) exhibited bilateral reductions in baseline activity within cortico-basal ganglia-thalamic regions associated with reward processing compared to wild-type controls (WT, C57BL/6 mice). Significant activity changes were not evident in regions either outside of the cortico-basal ganglia-thalamic network or within the network that are not associated with reward processing. Parallel studies demonstrated that reward network hypoactivity in DKO mice predicted a significant attenuation in consumption and preference levels to escalating ethanol concentrations (12, 20 and 30%) compared to WT mice, an effect that was maintained over extended access (14 sessions) to 20% ethanol. Summarizing, these data support a contribution of AC1 and 8 in cortico-basal ganglia-thalamic activity and the predictive value of this regulatory influence on ethanol drinking behavior, which merits the future evaluation of calcium-stimulated ACs in the neural processes that engender vulnerability to maladaptive alcohol drinking.

KEYWORDS:

Adenylyl cyclase; Calcium; Cortico-basal ganglia-thalamic; Ethanol; Magnetic resonance imaging; Manganese

5.
Brain Struct Funct. 2018 Jun;223(5):2343-2360. doi: 10.1007/s00429-018-1635-z. Epub 2018 Feb 27.

Tinnitus and temporary hearing loss result in differential noise-induced spatial reorganization of brain activity.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 550 East Canfield Ave., Detroit, MI, 48201, USA.
2
Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
4
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, 550 East Canfield Ave., Detroit, MI, 48201, USA. agholt@med.wayne.edu.
5
John D. Dingell VAMC, Detroit, MI, USA. agholt@med.wayne.edu.

Abstract

Loud noise frequently results in hyperacusis or hearing loss (i.e., increased or decreased sensitivity to sound). These conditions are often accompanied by tinnitus (ringing in the ears) and changes in spontaneous neuronal activity (SNA). The ability to differentiate the contributions of hyperacusis and hearing loss to neural correlates of tinnitus has yet to be achieved. Towards this purpose, we used a combination of behavior, electrophysiology, and imaging tools to investigate two models of noise-induced tinnitus (either with temporary hearing loss or with permanent hearing loss). Manganese (Mn2+) uptake was used as a measure of calcium channel function and as an index of SNA. Manganese uptake was examined in vivo with manganese-enhanced magnetic resonance imaging (MEMRI) in key auditory brain regions implicated in tinnitus. Following acoustic trauma, MEMRI, the SNA index, showed evidence of spatially dependent rearrangement of Mn2+ uptake within specific brain nuclei (i.e., reorganization). Reorganization of Mn2+ uptake in the superior olivary complex and cochlear nucleus was dependent upon tinnitus status. However, reorganization of Mn2+ uptake in the inferior colliculus was dependent upon hearing sensitivity. Furthermore, following permanent hearing loss, reduced Mn2+ uptake was observed. Overall, by combining testing for hearing sensitivity, tinnitus, and SNA, our data move forward the possibility of discriminating the contributions of hyperacusis and hearing loss to tinnitus.

KEYWORDS:

Acoustic startle reflex; Gap detection; Hearing loss; Hyperactivity; Hyperacusis; MEMRI; Manganese enhanced MRI; Neuronal activity; Neuroplasticity; Permanent threshold shift; Temporary threshold shift; Tinnitus

6.
NMR Biomed. 2018 Mar;31(3). doi: 10.1002/nbm.3887. Epub 2018 Jan 12.

Development of manganese-enhanced magnetic resonance imaging of the rostral ventrolateral medulla of conscious rats: Importance of normalization and comparison with other regions of interest.

Author information

1
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, USA.
2
Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
4
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
5
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
6
John Dingell Veterans Administration Medical Center, Detroit, MI, USA.

Abstract

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are believed to contribute to pathophysiological alterations in sympathetic nerve activity and the development of cardiovascular disease. The ability to identify changes in the activity of RVLM neurons in conscious animals and humans, especially longitudinally, would represent a clinically important advancement in our understanding of the contribution of the RVLM to cardiovascular disease. To this end, we describe the initial development of manganese-enhanced magnetic resonance imaging (MEMRI) for the rat RVLM. Manganese (Mn2+ ) has been used to estimate in vivo neuronal activity in other brain regions because of both its paramagnetic properties and its entry into and accumulation in active neurons. In this initial study, our three goals were as follows: (1) to validate that Mn2+ enhancement occurs in functionally and anatomically localized images of the rat RVLM; (2) to quantify the dose and time course dependence of Mn2+ enhancement in the RVLM after one systemic injection in conscious rats (66 or 33 mg/kg, intraperitoneally); and (3) to compare Mn2+ enhancement in the RVLM with other regions to determine an appropriate method of normalization of T1 -weighted images. In our proof-of-concept and proof-of-principle studies, Mn2+ was identified by MRI in the rat RVLM after direct microinjection or via retrograde transport following spinal cord injections, respectively. Systemic injections in conscious rats produced significant Mn2+ enhancement at 24 h (p < 0.05). Injections of 66 mg/kg produced greater enhancement than 33 mg/kg in the RVLM and paraventricular nucleus of the hypothalamus (p < 0.05 for both), but only when normalized to baseline scans without Mn2+ injection. Consistent with findings from our previous functional and anatomical studies demonstrating subregional neuroplasticity, Mn2+ enhancement was higher in the rostral regions of the RVLM (p < 0.05). Together with important technical considerations, our studies support the development of MEMRI as a potential method to examine RVLM activity over time in conscious animal subjects.

KEYWORDS:

brainstem; conscious; imaging; in vivo; neuronal activity

PMID:
29327782
PMCID:
PMC5819885
[Available on 2019-03-01]
DOI:
10.1002/nbm.3887
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7.
Invest Ophthalmol Vis Sci. 2017 Jun 1;58(7):3286-3293. doi: 10.1167/iovs.17-21850.

Sodium Iodate Produces a Strain-Dependent Retinal Oxidative Stress Response Measured In Vivo Using QUEST MRI.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Deptarment of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, United States.
3
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, United States.

Abstract

Purpose:

We identify noninvasive biomarkers that measure the severity of oxidative stress within retina layers in sodium iodate (SI)-atrophy vulnerable (C57BL/6 [B6]) and SI-atrophy resistant (129S6/SvEvTac [S6]) mice.

Methods:

At 24 hours after administering systemic SI to B6 and S6 mice we measured: (1) superoxide production in whole retina ex vivo, (2) excessive free radical production in vivo based on layer-specific 1/T1 values before and after α-lipoic acid (ALA) administration while the animal was inside the magnet (QUEnch-assiSTed MRI [QUEST MRI]), and (3) visual performance (optokinetic tracking) ± antioxidants; control mice were similarly assessed. Retinal layer spacing and thickness in vivo also were evaluated (optical coherence tomography, MRI).

Results:

SI-treated B6 mice retina had a significantly higher superoxide production than SI-treated S6 mice. ALA-injected SI-treated B6 mice had reduced 1/T1 in more retinal layers in vivo than in SI-treated S6 mice. Uninjected and saline-injected SI-treated B6 mice had similar transretinal 1/T1 profiles. Notably, the inner segment layer 1/T1 of SI-treated B6 mice was responsive to ALA but was unresponsive in SI-treated S6 mice. In both SI-treated strains, antioxidants improved contrast sensitivity to similar extents; antioxidants did not change acuity in either group. Retinal thicknesses were normal in both SI-treated strains at 24 hours after treatment.

Conclusions:

QUEST MRI uniquely measured severity of excessive free radical production within retinal layers of the same subject. Identifying the mechanisms underlying genetic vulnerabilities to oxidative stress is expected to help in understanding the pathogenesis of retinal degeneration.

PMID:
28666279
PMCID:
PMC5493331
DOI:
10.1167/iovs.17-21850
[Indexed for MEDLINE]
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8.
FASEB J. 2017 Sep;31(9):4179-4186. doi: 10.1096/fj.201700229R. Epub 2017 Jun 7.

In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, USA; baberko@med.wayne.edu.
2
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, USA.
3
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, Michigan, USA.
4
Department of Radiology, Wayne State University, Detroit, Michigan, USA.
5
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, USA.
6
Department of Pharmacology and Nutritional Sciences, University of Kentucky Medical Center, Lexington, Kentucky, USA.
7
Department of Molecular and Integrative Physiology, Molecular Behavioral Neuroscience Institute, University of Michigan Medical School, Ann Arbor, Michigan, USA.
8
Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.

Abstract

Hippocampus oxidative stress is considered pathogenic in neurodegenerative diseases, such as Alzheimer disease (AD), and in neurodevelopmental disorders, such as Angelman syndrome (AS). Yet clinical benefits of antioxidant treatment for these diseases remain unclear because conventional imaging methods are unable to guide management of therapies in specific hippocampus subfields in vivo that underlie abnormal behavior. Excessive production of paramagnetic free radicals in nonhippocampus brain tissue can be measured in vivo as a greater-than-normal 1/T1 that is quenchable with antioxidant as measured by quench-assisted (Quest) MRI. Here, we further test this approach in phantoms, and we present proof-of-concept data in models of AD-like and AS hippocampus oxidative stress that also exhibit impaired spatial learning and memory. AD-like models showed an abnormal gradient along the CA1 dorsal-ventral axis of excessive free radical production as measured by Quest MRI, and redox-sensitive calcium dysregulation as measured by manganese-enhanced MRI and electrophysiology. In the AS model, abnormally high free radical levels were observed in dorsal and ventral CA1. Quest MRI is a promising in vivo paradigm for bridging brain subfield oxidative stress and behavior in animal models and in human patients to better manage antioxidant therapy in devastating neurodegenerative and neurodevelopmental diseases.-Berkowitz, B. A., Lenning, J., Khetarpal, N., Tran, C., Wu, J. Y., Berri, A. M., Dernay, K., Haacke, E. M., Shafie-Khorassani, F., Podolsky, R. H., Gant, J. C., Maimaiti, S., Thibault, O., Murphy, G. G., Bennett, B. M., Roberts, R. In vivo imaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome.

KEYWORDS:

MRI; dorsoventral CA1; neurodegenerative disease; neurodevelopment disorders; reactive oxygen species

PMID:
28592637
DOI:
10.1096/fj.201700229R
[Indexed for MEDLINE]
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9.
Neurobiol Aging. 2017 Jan;49:198-203. doi: 10.1016/j.neurobiolaging.2016.09.009. Epub 2016 Sep 23.

Genetically heterogeneous mice show age-related vision deficits not related to increased rod cell L-type calcium channel function in vivo.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA; Department Of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: baberko@med.wayne.edu.
2
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
3
Department Of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

Visual performance declines over time in humans and 2-18 months outbred Long-Evans (LE) rats; vision is maintained in inbred 2-18 months C57BL/6 (B6) mice. Increased rod L-type calcium channel (LTCC) function predicts visual decline in LE rats but does not occur in B6 mice. Genetic diversity may contribute to rod LTCC function escalation time. To test this hypothesis, 4 and 18 months genetically heterogeneous UM-HET3 mice were studied. Rod LTCC function (manganese-enhanced magnetic resonance imaging [MRI]) and ocular anatomy (MRI, optical coherence tomography) were measured in vivo. Light-evoked subretinal space and choroid thickness changes were measured (diffusion-weighted MRI). Visual performance declined over time in the absence of (1) increased rod LTCC function; (2) changes in light-dependent expansion of the subretinal space and choroidal thickness; and (3) retinal thinning. Aging changed anterior and vitreous chambers' axial length and decreased light-stimulated choroidal expansion. Species differences appear to contribute to the LTCC function differences. Aging-related declines in vision in the UM-HET3 mice deserve more attention than they have received so far.

KEYWORDS:

Aging; MEMRI; OKT; Retina

[Indexed for MEDLINE]
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10.
Invest Ophthalmol Vis Sci. 2016 Oct 1;57(13):5314-5319. doi: 10.1167/iovs.16-20186.

Melanopsin Phototransduction Contributes to Light-Evoked Choroidal Expansion and Rod L-Type Calcium Channel Function In Vivo.

Author information

1
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.
2
Department of Neurobiology, Northwestern University, Evanston, Illinois, United States.
3
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan, United States.
4
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States.

Abstract

Purpose:

In humans, rodents, and pigeons, the dark → light transition signals nonretinal brain tissue to increase choroidal thickness, a major control element of choroidal blood flow, and thus of photoreceptor and retinal pigment epithelium function. However, it is unclear which photopigments in the retina relay the light signal to the brain. Here, we test the hypothesis that melanopsin (Opn4)-regulated phototransduction modulates light-evoked choroidal thickness expansion in mice.

Methods:

Two-month-old C57Bl/6 wild-type (B6), 4- to 5-month-old C57Bl/6/129S6 wild-type (B6 + S6), and 2-month-old melanopsin knockout (Opn4-/-) on a B6 + S6 background were studied. Retinal anatomy was evaluated in vivo by optical coherence tomography and MRI. Choroidal thickness in dark and light were measured by diffusion-weighted MRI. Rod cell L-type calcium channel (LTCC) function in dark and light (manganese-enhanced MRI [MEMRI]) was also measured.

Results:

Opn4-/- mice did not show the light-evoked expansion of choroidal thickness observed in B6 and B6 + S6 controls. Additionally, Opn4-/- mice had lower than normal rod cell and inner retinal LTCC function in the dark but not in the light. These deficits were not due to structural abnormalities because retinal laminar architecture and thickness, and choroidal thickness in the Opn4-/- mice were similar to controls.

Conclusions:

First time evidence is provided that melanopsin phototransduction contributes to dark → light control of murine choroidal thickness. The data also highlight a contribution in vivo of melanopsin phototransduction to rod cell and inner retinal depolarization in the dark.

PMID:
27727394
PMCID:
PMC5063053
DOI:
10.1167/iovs.16-20186
[Indexed for MEDLINE]
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11.
Proc Natl Acad Sci U S A. 2016 Apr 5;113(14):3885-90. doi: 10.1073/pnas.1515895113. Epub 2016 Mar 22.

Differential volume regulation and calcium signaling in two ciliary body cell types is subserved by TRPV4 channels.

Author information

1
Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132;
2
Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48202;
3
Department of Anatomy and Cell Biology, Wayne State University, Detroit, MI 48202; Department of Ophthalmology, Wayne State University, Detroit, MI 48202;
4
Department of Ophthalmology & Visual Sciences, University of Utah School of Medicine, Salt Lake City, UT 84132; Center for Translational Medicine, Moran Eye Institute, University of Utah, Salt Lake City, UT 84132; Department of Neurobiology & Anatomy, University of Utah, Salt Lake City, UT 84132; Department of Bioengineering, University of Utah, Salt Lake City, UT 84132 david.krizaj@hsc.utah.edu.

Abstract

Fluid secretion by the ciliary body plays a critical and irreplaceable function in vertebrate vision by providing nutritive support to the cornea and lens, and by maintaining intraocular pressure. Here, we identify TRPV4 (transient receptor potential vanilloid isoform 4) channels as key osmosensors in nonpigmented epithelial (NPE) cells of the mouse ciliary body. Hypotonic swelling and the selective agonist GSK1016790A (EC50 ∼33 nM) induced sustained transmembrane cation currents and cytosolic [Formula: see text] elevations in dissociated and intact NPE cells. Swelling had no effect on [Formula: see text] levels in pigment epithelial (PE) cells, whereas depolarization evoked [Formula: see text] elevations in both NPE and PE cells. Swelling-evoked [Formula: see text] signals were inhibited by the TRPV4 antagonist HC067047 (IC50 ∼0.9 μM) and were absent in Trpv4(-/-) NPE. In NPE, but not PE, swelling-induced [Formula: see text] signals required phospholipase A2 activation. TRPV4 localization to NPE was confirmed with immunolocalization and excitation mapping approaches, whereas in vivo MRI analysis confirmed TRPV4-mediated signals in the intact mouse ciliary body. Trpv2 and Trpv4 were the most abundant vanilloid transcripts in CB. Overall, our results support a model whereby TRPV4 differentially regulates cell volume, lipid, and calcium signals in NPE and PE cell types and therefore represents a potential target for antiglaucoma medications.

KEYWORDS:

TRPV4; aqueous humor; ciliary body; glaucoma; intraocular pressure

PMID:
27006502
PMCID:
PMC4833269
DOI:
10.1073/pnas.1515895113
[Indexed for MEDLINE]
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12.
Invest Ophthalmol Vis Sci. 2016 Feb;57(2):577-85. doi: 10.1167/iovs.15-18972.

MRI of Retinal Free Radical Production With Laminar Resolution In Vivo.

Author information

1
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Department of Molecular Genetics and Microbiology, University of Florida, Gainesville, Florida, United States.
3
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.

Abstract

PURPOSE:

Recent studies have suggested the hypothesis that quench-assisted 1/T1 magnetic resonance imaging (MRI) measures free radical production with laminar resolution in vivo without the need of a contrast agent. Here, we test this hypothesis further by examining the spatial and detection sensitivity of quench-assisted 1/T1 MRI to strain, age, or retinal cell layer-specific genetic manipulations.

METHODS:

We studied: adult wild-type mice; mice at postnatal day 7 (P7); cre dependent retinal pigment epithelium (RPE)-specific MnSOD knockout mice; doxycycline-treated Sod2f(lox/flox) mice lacking the cre transgene; and α-transducin knockout (Gnat1(-/-)) mice on a C57Bl/6 background. Transretinal 1/T1 profiles were mapped in vivo in the dark without or with antioxidant treatment, or followed by light exposure. We calibrated profiles spatially using optical coherence tomography.

RESULTS:

Dark-adapted RPE-specific MnSOD knockout mice had greater than normal 1/T1 in the RPE and outer nuclear layers that was corrected to wild-type levels by antioxidant treatment. Dark and light Gnat1(-/-) mice also had greater than normal outer retinal 1/T1 values. In adult wild-type mice, dark values of 1/T1 in the ellipsoid region and in the outer segment were suppressed by 13 minutes of light. By 29 minutes of light, 1/T1 reduction extended to the outer nuclear layer. Gnat1(-/-) mice demonstrated a faster light-evoked suppression of 1/T1 values in the outer retina. In P7 mice, transretinal 1/T1 profiles were the same in dark and light.

CONCLUSIONS:

Quench-assisted MRI has the laminar resolution and detection sensitivity to evaluate normal and pathologic production of free radicals in vivo.

PMID:
26886890
PMCID:
PMC4771178
DOI:
10.1167/iovs.15-18972
[Indexed for MEDLINE]
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13.
Invest Ophthalmol Vis Sci. 2015 Dec;56(13):7931-8. doi: 10.1167/iovs.15-18420.

Measuring In Vivo Free Radical Production by the Outer Retina.

Author information

1
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
3
Laboratory for Retinal Cell Biology, Department of Ophthalmology, University of Zurich, Switzerland.

Abstract

PURPOSE:

Excessive and continuously produced free radicals in the outer retina are implicated in retinal aging and the pathogenesis of sight-threatening retinopathies, yet measuring outer retinal oxidative stress in vivo remains a challenge. Here, we test the hypothesis that continuously produced paramagnetic free radicals from the outer retina can be measured in vivo using high-resolution (22-μm axial resolution) 1/T1magnetic resonance imaging (MRI) without and with a confirmatory quench (quench-assisted MRI).

METHODS:

Low-dose sodium iodate-treated and diabetic C57Bl6/J mice (and their controls), and rod-dominated (129S6) or cone-only R91W;Nrl-/- mice were studied. In dark-adapted groups, 1/T1 was mapped transretinally in vivo without or with (1) the antioxidant combination of methylene blue (MB) and α-lipoic acid (LPA), or (2) light exposure; in subgroups, retinal superoxide production was measured ex vivo (lucigenin).

RESULTS:

In the sodium iodate model, retinal superoxide production and outer retina-specific 1/T1 values were both significantly greater than normal and corrected to baseline with MB+LPA therapy. Nondiabetic mice at two ages and 1.2-month diabetic mice (before the appearance of oxidative stress) had similar transretinal 1/T1 profiles. By 2.3 months of diabetes, only outer retinal 1/T1 values were significantly greater than normal and were corrected to baseline with MB+LPA therapy. In mice with healthy photoreceptors, a light quench caused 1/T1 of rods, but not cones, to significantly decrease from their values in the dark.

CONCLUSIONS:

Quench-assisted MRI is a feasible method for noninvasively measuring normal and pathologic production of free radicals in photoreceptors/RPE in vivo.

PMID:
26670830
PMCID:
PMC4682605
DOI:
10.1167/iovs.15-18420
[Indexed for MEDLINE]
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14.
Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6294-303. doi: 10.1167/iovs.15-16990.

Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice.

Author information

1
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio, United States.
3
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.
4
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, United States.

Abstract

PURPOSE:

Diabetes appears to induce a visual cycle defect because rod dysfunction is correctable with systemic treatment of the visual cycle chromophore 11-cis-retinaldehyde. However, later studies have found no evidence for visual cycle impairment. Here, we further examined whether photoreceptor dysfunction is corrected with 11-cis-retinaldehyde. Because antioxidants correct photoreceptor dysfunction in diabetes, the hypothesis that exogenous visual chromophores have antioxidant activity in the retina of diabetic mice in vivo was tested.

METHODS:

Rod function in 2-month-old diabetic mice was evaluated using transretinal electrophysiology in excised retinas and apparent diffusion coefficient (ADC) MRI to measure light-evoked expansion of subretinal space (SRS) in vivo. Optokinetic tracking was used to evaluate cone-based visual performance. Retinal production of superoxide free radicals, generated mostly in rod cells, was biochemically measured with lucigenin. Diabetic mice were systemically treated with a single injection of either 11-cis-retinaldehyde, 9-cis-retinaldehyde (a chromophore surrogate), or all-trans-retinaldehyde (the photoisomerization product of 11-cis-retinaldehyde).

RESULTS:

Consistent with previous reports, diabetes significantly reduced (1) dark-adapted rod photo responses (transretinal recording) by ∼18%, (2) rod-dominated light-stimulated SRS expansion (ADC MRI) by ∼21%, and (3) cone-dominated contrast sensitivity (using optokinetic tracking [OKT]) by ∼30%. Both 11-cis-retinaldehyde and 9-cis-retinaldehyde largely corrected these metrics of photoreceptor dysfunction. Higher-than-normal retinal superoxide production in diabetes by ∼55% was also significantly corrected following treatment with 11-cis-retinaldehyde, 9-cis-retinaldehyde, or all-trans-retinaldehyde.

CONCLUSIONS:

Collectively, data suggest that retinaldehydes improve photoreceptor dysfunction in diabetic mice, independent of the visual cycle, via an antioxidant mechanism.

PMID:
26431483
PMCID:
PMC4594469
DOI:
10.1167/iovs.15-16990
[Indexed for MEDLINE]
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15.
PLoS One. 2015 Oct 1;10(10):e0139003. doi: 10.1371/journal.pone.0139003. eCollection 2015.

Photobiomodulation Mitigates Diabetes-Induced Retinopathy by Direct and Indirect Mechanisms: Evidence from Intervention Studies in Pigmented Mice.

Author information

1
Case Western Reserve University, Cleveland, Ohio, United States of America; Catholic University of Brasilia, Brasilia, Brazil.
2
Case Western Reserve University, Cleveland, Ohio, United States of America.
3
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States of America.
4
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States of America; Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States of America.
5
Case Western Reserve University, Cleveland, Ohio, United States of America; Cleveland Veteran's Affairs Medical Center, Research Service 151, Cleveland, Ohio, United States of America.

Abstract

OBJECTIVE:

Daily application of far-red light from the onset of diabetes mitigated diabetes-induced abnormalities in retinas of albino rats. Here, we test the hypothesis that photobiomodulation (PBM) is effective in diabetic, pigmented mice, even when delayed until weeks after onset of diabetes. Direct and indirect effects of PBM on the retina also were studied.

METHODS:

Diabetes was induced in C57Bl/6J mice using streptozotocin. Some diabetics were exposed to PBM therapy (4 min/day; 670 nm) daily. In one study, mice were diabetic for 4 weeks before initiation of PBM for an additional 10 weeks. Retinal oxidative stress, inflammation, and retinal function were measured. In some mice, heads were covered with a lead shield during PBM to prevent direct illumination of the eye, or animals were treated with an inhibitor of heme oxygenase-1. In a second study, PBM was initiated immediately after onset of diabetes, and administered daily for 2 months. These mice were examined using manganese-enhanced MRI to assess effects of PBM on transretinal calcium channel function in vivo.

RESULTS:

PBM intervention improved diabetes-induced changes in superoxide generation, leukostasis, expression of ICAM-1, and visual performance. PBM acted in part remotely from the retina because the beneficial effects were achieved even with the head shielded from the light therapy, and because leukocyte-mediated cytotoxicity of retinal endothelial cells was less in diabetics treated with PBM. SnPP+PBM significantly reduced iNOS expression compared to PBM alone, but significantly exacerbated leukostasis. In study 2, PBM largely mitigated diabetes-induced retinal calcium channel dysfunction in all retinal layers.

CONCLUSIONS:

PBM induces retinal protection against abnormalities induced by diabetes in pigmented animals, and even as an intervention. Beneficial effects on the retina likely are mediated by both direct and indirect mechanisms. PBM is a novel non-pharmacologic treatment strategy to inhibit early changes of diabetic retinopathy.

PMID:
26426815
PMCID:
PMC4591336
DOI:
10.1371/journal.pone.0139003
[Indexed for MEDLINE]
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16.
NMR Biomed. 2015 Nov;28(11):1480-8. doi: 10.1002/nbm.3409. Epub 2015 Sep 28.

Cocaine-induced locomotor sensitization in rats correlates with nucleus accumbens activity on manganese-enhanced MRI.

Author information

1
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI, USA.
2
Department of Anesthesiology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI, USA.
4
Research and Development Service, John D. Dingell Veterans Affairs Medical Center, Detroit, MI, USA.
5
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
6
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

A long-standing goal of substance abuse research has been to link drug-induced behavioral outcomes with the activity of specific brain regions to understand the neurobiology of addiction behaviors and to search for drug-able targets. Here, we tested the hypothesis that cocaine produces locomotor (behavioral) sensitization that correlates with increased calcium channel-mediated neuroactivity in brain regions linked with drug addiction, such as the nucleus accumbens (NAC), anterior striatum (AST) and hippocampus, as measured using manganese-enhanced MRI (MEMRI). Rats were treated with cocaine for 5 days, followed by a 2-day drug-free period. The following day, locomotor sensitization was quantified as a metric of cocaine-induced neuroplasticity in the presence of manganese. Immediately following behavioral testing, rats were examined for changes in calcium channel-mediated neuronal activity in the NAC, AST, hippocampus and temporalis muscle, which was associated with behavioral sensitization using MEMRI. Cocaine significantly increased locomotor activity and produced behavioral sensitization compared with saline treatment of control rats. A significant increase in MEMRI signal intensity was determined in the NAC, but not AST or hippocampus, of cocaine-treated rats compared with saline-treated control rats. Cocaine did not increase signal intensity in the temporalis muscle. Notably, in support of our hypothesis, behavior was significantly and positively correlated with MEMRI signal intensity in the NAC. As neuronal uptake of manganese is regulated by calcium channels, these results indicate that MEMRI is a powerful research tool to study neuronal activity in freely behaving animals and to guide new calcium channel-based therapies for the treatment of cocaine abuse and dependence.

KEYWORDS:

behavioral sensitization; calcium; cocaine; dopamine transporter; magnetic resonance imaging; manganese; nucleus accumbens; striatum

PMID:
26411897
PMCID:
PMC4618766
DOI:
10.1002/nbm.3409
[Indexed for MEDLINE]
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17.
Prog Retin Eye Res. 2016 Mar;51:90-106. doi: 10.1016/j.preteyeres.2015.09.001. Epub 2015 Sep 4.

MRI of rod cell compartment-specific function in disease and treatment in vivo.

Author information

1
Dept. of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA; Dept. Of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA. Electronic address: baberko@med.wayne.edu.
2
Dept. of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA.
3
Dept. Of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract

Rod cell oxidative stress is a major pathogenic factor in retinal disease, such as diabetic retinopathy (DR) and retinitis pigmentosa (RP). Personalized, non-destructive, and targeted treatment for these diseases remains elusive since current imaging methods cannot analytically measure treatment efficacy against rod cell compartment-specific oxidative stress in vivo. Over the last decade, novel MRI-based approaches that address this technology gap have been developed. This review summarizes progress in the development of MRI since 2006 that enables earlier evaluation of the impact of disease on rod cell compartment-specific function and the efficacy of anti-oxidant treatment than is currently possible with other methods. Most of the new assays of rod cell compartment-specific function are based on endogenous contrast mechanisms, and this is expected to facilitate their translation into patients with DR and RP, and other oxidative stress-based retinal diseases.

KEYWORDS:

Animal models; Calcium channels; Diabetes; MRI; Retinitis pigmentosa; Retinopathy; Subretinal space; Vision

[Indexed for MEDLINE]
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18.
J Diabetes Investig. 2015 Jul;6(4):371-80. doi: 10.1111/jdi.12312. Epub 2015 Jan 7.

Photoreceptors in diabetic retinopathy.

Author information

1
Case Western Reserve University, Department of Medicine and Center for Diabetes Research Cleveland, Ohio, USA ; Veterans Administration Medical Center Research Service 151 Cleveland, Ohio, USA.
2
Wayne State University School of Medicine, Departments of Anatomy and Cell Biology and Ophthalmology Detroit, Michigan, USA.

Abstract

Although photoreceptors account for most of the mass and metabolic activity of the retina, their role in the pathogenesis of diabetic retinopathy has been largely overlooked. Recent studies suggest that photoreceptors might play a critical role in the diabetes-induced degeneration of retinal capillaries, and thus can no longer be ignored. The present review summarizes diabetes-induced alterations in photoreceptor structure and function, and provides a rationale for further study of a role of photoreceptors in the pathogenesis of the retinopathy.

KEYWORDS:

Diabetes; Diabetic retinopathy; Photoreceptors

19.
Invest Ophthalmol Vis Sci. 2015 May;56(5):3132-9. doi: 10.1167/iovs.15-16581.

Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo.

Author information

1
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States 2Department of Ophthalmology, Wayne State University School of Medicine, Detroit, Michigan, United States.
2
University of Michigan Medical School, Molecular Behavioral Neuroscience Institute, Molecular and Integrative Physiology, Ann Arbor, Michigan, United States.
3
Mary D. Allen Laboratory for Vision Research, USC Eye Institute, and Department of Ophthalmology and Department of Cell and Neurobiology, Keck School of Medicine of the University of Southern California, Los Angeles, California, United States.
4
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States.
5
Department of Anatomy and Cell Biology Wayne State University School of Medicine, Detroit, Michigan, United States.

Abstract

PURPOSE:

To test the hypothesis that horizontal cell (HC) inhibitory signaling controls the degree to which rod cell membranes are depolarized as measured by the extent to which L-type calcium channels (LTCCs) are open in complete darkness in the mouse retina in vivo.

METHODS:

Dark-adapted wild-type (wt), CACNA1F (Ca(v)1.4(-/-)), arrestin-1 (Arr1(-/-)), and CACNA1D (Ca(v)1.3(-/-)) C57Bl/6 mice were studied. Manganese-enhanced MRI (MEMRI) evaluated the extent that rod LTCCs are open as an index of loss of HC inhibitory signaling. Subgroups were pretreated with D-cis-diltiazem (DIL) at a dose that specifically antagonizes Ca(v)1.2 channels in vivo.

RESULTS:

Knockout mice predicted to have impaired HC inhibitory signaling (Ca(v)1.4(-/-) or Arr1(-/-)) exhibited greater than normal rod manganese uptake; inner retinal uptake was also supernormal. Genetically knocking out a closely associated gene not expected to impact HC inhibitory signaling (CACNA1D) did not generate this phenotype. The Arr1(-/-) mice exhibited the largest rod uptake of manganese. Manganese-enhanced MRI of DIL-treated Arr1(-/-) mice suggested a greater number of operant LTCC subtypes (i.e., Ca(v)1.2, 1.3, and 1.4) in rods and inner retina than that in DIL-treated Ca(v)1.4(-/-) mice (i.e., Ca(v)1.3). The Ca(v)1.3(-/-) + DIL-treated mice exhibited evidence for a compensatory contribution from Ca(v)1.2 LTCCs.

CONCLUSIONS:

The data suggest that loss of HC inhibitory signaling is the proximate cause leading to maximally open LTCCs in rods, and possibly inner retinal cells, in mice in total darkness in vivo, regardless of compensatory changes in LTCC subtype manifested in the mutant mice.

PMID:
26024096
PMCID:
PMC4451614
DOI:
10.1167/iovs.15-16581
[Indexed for MEDLINE]
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20.
Invest Ophthalmol Vis Sci. 2015 May;56(5):3095-102. doi: 10.1167/iovs.14-16194.

Catalase therapy corrects oxidative stress-induced pathophysiology in incipient diabetic retinopathy.

Author information

1
Department of Pharmacology, Wayne State University, Detroit, Michigan, United States.
2
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States.
3
Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.
4
Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, United States 3Department of Ophthalmology, Wayne State University, Detroit, Michigan, United States.

Abstract

PURPOSE:

Preclinical studies have highlighted retinal oxidative stress in the pathogenesis of diabetic retinopathy. We evaluated whether a treatment designed to enhance cellular catalase reduces oxidative stress in retinal cells cultured in high glucose and in diabetic mice corrects an imaging biomarker responsive to antioxidant therapy (manganese-enhanced magnetic resonance imaging [MEMRI]).

METHODS:

Human retinal Müller and pigment epithelial cells were chronically exposed to normal or high glucose levels and treated with a cell-penetrating derivative of the peroxisomal enzyme catalase (called CAT-SKL). Hydrogen peroxide (H2O2) levels were measured using a quantitative fluorescence-based assay. For in vivo studies, streptozotocin (STZ)-induced diabetic C57Bl/6 mice were treated subcutaneously once a week for 3 to 4 months with CAT-SKL; untreated age-matched nondiabetic controls and untreated diabetic mice also were studied. MEMRI was used to analytically assess the efficacy of CAT-SKL treatment on diabetes-evoked oxidative stress-related pathophysiology in vivo. Similar analyses were performed with difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase.

RESULTS:

After catalase transduction, high glucose-induced peroxide production was significantly lowered in both human retinal cell lines. In diabetic mice in vivo, subnormal intraretinal uptake of manganese was significantly improved by catalase supplementation. In addition, in the peroxisome-rich liver of treated mice catalase enzyme activity increased and oxidative damage (as measured by lipid peroxidation) declined. On the other hand, DFMO was largely without effect in these in vitro or in vivo assays.

CONCLUSIONS:

This proof-of-concept study raises the possibility that augmentation of catalase is a therapy for treating the retinal oxidative stress associated with diabetic retinopathy.

PMID:
25813998
PMCID:
PMC4439131
DOI:
10.1167/iovs.14-16194
[Indexed for MEDLINE]
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